8-溴-2,3,4,5-四氢-3-甲基-5-苯基-1H-3-苯并氮杂-7-醇 | 99295-33-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯氮卓类
• 中文名称: 8-溴-2,3,4,5-四氢-3-甲基-5-苯基-1H-3-苯并氮杂-7-醇
• 英文名称: SKF 83566
• 英文别名: 8-Bromo-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol；8-bromo-3-methyl-5-phenyl-1,2,4,5-tetrahydro-3-benzazepin-7-ol
• CAS: 99295-33-7
• 化学式: C₁₇H₁₈BrNO
• 分子量: 332.24
• InChiKey: XFTVOHWWEQGXLS-UHFFFAOYSA-N

物化性质

• 溶解度：
  45%(w/v)aq2-羟丙基-β-环糊精：≥14 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  23.5
• 氢给体数：
  1
• 氢受体数：
  2

安全信息

• WGK Germany：
  3
• 海关编码：
  2933990090

制备方法与用途

生物活性

SKF-83566 是一种有效的、能够透过血脑屏障且具有口服活性的 D1 样多巴胺受体 (D1-like dopamine receptor) 拮抗剂，同时也能作为一种较弱的竞争性拮抗剂作用于血管 5-HT2 受体 (Ki = 11 nM)。SKF-83566 还是一种竞争性多巴胺转运蛋白 (DAT) 抑制剂，IC50 为 5.7 μM。在离体兔胸主动脉中，它对腺苷基环化酶 2 (AC2) 的选择性高于对 AC1 和 AC5 的作用。SKF-83566 可用于研究帕金森氏症和尼古丁渴望的缓解。

靶点

	D1 Receptor	D5 Receptor	5-HT2 Receptor (Ki = 11 nM)

体外研究

SKF-83566（0.1 μM-10 μM）能引起单脉冲刺激下外周多巴胺浓度 ([DA]o) 浓度依赖性增加，最大可增加 65%。其 EC50 值为 1.3 μM。SKF-83566 抑制 [3H]DA 吸收，IC50 为 5.73 μM，并且比对 [3H]CFT（去甲肾上腺素类衍生物）结合的抑制作用更强，IC50 为 0.51 μM。在 LLc-PK-rDAT 细胞中，SKF-83566 对 [3H]CFT 结合的 IC50 值也为 0.77 μM。

体内研究

单独给予 SKF 83566 氢溴酸盐（口服；20 µg/mL；7 天）不会改变长期突触增强 (LTP)。然而，SKF 83566 和尼古丁的联合使用能显著阻止由尼古丁预处理引起的 LTP 增强 (143%)。

实验动物模型:	雄性 C57BL/6/J 小鼠（6-至9周龄）
剂量:	20 µg/mL（与尼古丁共同给药7天后注射可卡因）
给药方式:	口服；7 天
结果:	阻止了尼古丁和可卡因引起的 LTP 增强。

反应信息

• 作为反应物：
  描述：

  8-溴-2,3,4,5-四氢-3-甲基-5-苯基-1H-3-苯并氮杂-7-醇 在 quiral lux cellulose-1 column 作用下， 以 甲醇 、 甲酸 、 异丙醇 为溶剂， 生成 (S)-SKF 83566 、 (+)-(R)-8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol
  参考文献：
  名称：

  Molecular Modeling Evaluation of the Enantiomers of a Novel Adenylyl Cyclase 2 Inhibitor

  摘要：

  Adenylyl cyclase 2 (AC2) is one of nine membrane-bound isoforms of adenylyl cyclase that converts ATP into cyclic AMP (cAMP), an important second messenger molecule. Upregulation of AC2 is linked to cancers like pancreatic and small intestinal neuroendocrine tumors (NETS). The structures of the various isoforms of adenylyl cyclases are highly homologous, posing a significant challenge to drug discovery efforts for an effective, isoform-selective modulator of AC2. In a previous study, a screen identified a potential isoform-selective and noncompetitive inhibitor of AC2, SKF83566. In the present study, molecular modeling is used to explore the mode of inhibition of AC2 by SKF83566 and to investigate the active enantiomer of SKF83566. Homology models of hAC2 were built based on canine ACS-Cla and rat AC2-C2a templates. With these models, a combination of flexible docking, molecular dynamics simulations, and free energy calculations using the MM/GBSA methodology suggested an allosteric mechanism in which (S)-SKF83566 binds-to an allosteric site near ATP and alters the protein conformation of the ATP binding site, potentially preventing the adenosine moiety of ATP from forming an archlike shape to form cAMP. The predicted binding preference for the (S)-SKF83566 enantiomer and the predicted free energy are consistent with the experimental data.

  DOI：

  10.1021/acs.jcim.6b00454
• 作为产物：
  描述：

  [125I]-SKF 83692 、 溶剂黄146 以60%的产率得到
  参考文献：
  名称：

  DE JESUS O. T.; VAN MOFFAERT G. J.; GLOCK D.; GOLDBERG L. I.; FRIEDMAN A.+, J. LABBELLED COMPOUNDS AND RADIOPHARM., 23,(1986) N 9, 919-925

  摘要：

  DOI：

文献信息

• Molecular adjuvants for enhanced cytosolic delivery of active agents
  申请人：Universiteit Gent

  公开号：US11033572B2

  公开（公告）日：2021-06-15

  The present invention relates to a method and compositions for optimized intracellular delivery of active agents, in particular nucleic acids, using a specific class of adjuvants. The method and compositions of the invention enhance cytosolic release of the agents and can be used for the treatment of various disorders.

  本发明涉及一种使用特定类别佐剂优化活性剂（尤其是核酸）细胞内递送的方法和组合物。本发明的方法和组合物能增强药剂的细胞释放，可用于治疗各种疾病。
• MOLECULAR ADJUVANTS FOR ENHANCED CYTOSOLIC DELIVERY OF ACTIVE AGENTS
  申请人：Universiteit Gent

  公开号：US20190328768A1

  公开（公告）日：2019-10-31

  The present invention relates to a method and compositions for optimized intracellular delivery of active agents, in particular nucleic acids, using a specific class of adjuvants. The method and compositions of the invention enhance cytosolic release of the agents and can be used for the treatment of various disorders.
• [EN] MOLECULAR ADJUVANTS FOR ENHANCED CYTOSOLIC DELIVERY OF ACTIVE AGENTS<br/>[FR] ADJUVANTS MOLÉCULAIRES POUR L'ADMINISTRATION CYTOSOLIQUE AMÉLIORÉE D'AGENTS ACTIFS
  申请人：UNIV GENT

  公开号：WO2018134310A1

  公开（公告）日：2018-07-26

  The present invention relates to a method and compositions for optimized intracellular delivery of active agents, in particular nucleic acids, using a specific class of adjuvants. The method and compositions of the invention enhance cytosolic release of the agents and can be used for the treatment of various disorders.
• DE JESUS O. T.; VAN MOFFAERT G. J.; GLOCK D.; GOLDBERG L. I.; FRIEDMAN A.+, J. LABBELLED COMPOUNDS AND RADIOPHARM., 23,(1986) N 9, 919-925
  作者：DE JESUS O. T.、 VAN MOFFAERT G. J.、 GLOCK D.、 GOLDBERG L. I.、 FRIEDMAN A.+

  DOI：——

  日期：——
• Molecular Modeling Evaluation of the Enantiomers of a Novel Adenylyl Cyclase 2 Inhibitor
  作者：Neha Rana、Jason M. Conley、Monica Soto-Velasquez、Francisco León、Stephen J. Cutler、Val J. Watts、Markus A. Lill

  DOI：10.1021/acs.jcim.6b00454

  日期：2017.2.27

  Adenylyl cyclase 2 (AC2) is one of nine membrane-bound isoforms of adenylyl cyclase that converts ATP into cyclic AMP (cAMP), an important second messenger molecule. Upregulation of AC2 is linked to cancers like pancreatic and small intestinal neuroendocrine tumors (NETS). The structures of the various isoforms of adenylyl cyclases are highly homologous, posing a significant challenge to drug discovery efforts for an effective, isoform-selective modulator of AC2. In a previous study, a screen identified a potential isoform-selective and noncompetitive inhibitor of AC2, SKF83566. In the present study, molecular modeling is used to explore the mode of inhibition of AC2 by SKF83566 and to investigate the active enantiomer of SKF83566. Homology models of hAC2 were built based on canine ACS-Cla and rat AC2-C2a templates. With these models, a combination of flexible docking, molecular dynamics simulations, and free energy calculations using the MM/GBSA methodology suggested an allosteric mechanism in which (S)-SKF83566 binds-to an allosteric site near ATP and alters the protein conformation of the ATP binding site, potentially preventing the adenosine moiety of ATP from forming an archlike shape to form cAMP. The predicted binding preference for the (S)-SKF83566 enantiomer and the predicted free energy are consistent with the experimental data.